GER and Aspiration in Interstitial Lung Disease

Part of the Respiratory Medicine book series (RM, volume 2)


Many investigations have linked gastroesophageal reflux (GER) to various forms of interstitial lung disease (ILD) including idiopathic pulmonary fibrosis (IPF), scleroderma, and other connective tissue diseases (CTD). However, definitive proof that abnormal GER and microaspiration is a cause of ILD, promotes disease progression, or precipitates acute exacerbation of IPF or other forms of ILD is lacking. Nonetheless, evidence is accumulating that suggests that abnormal GER and microaspiration of refluxed gastroduodenal secretions may play a significant role in IPF, scleroderma, and other ILD. This chapter examines the published evidence and provides an assessment of the current state of knowledge of the role of GER and microaspiration in ILD.


Gastroesophageal reflux (GER) Aspiration Interstitial lung disease Pulmonary fibrosis (IPF) Scleroderma Connective tissue diseases (CTD) Microaspiration 


  1. 1.
    Tobin RW, Pope II CE, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158:1804–8.PubMedGoogle Scholar
  2. 2.
    Lee JS, Ryu JH, Elicker BM, Lydell CP, Jones KD, Wolters PJ, et al. Gastroesophageal reflux therapy is associated with longer survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184:1390–4.CrossRefPubMedGoogle Scholar
  3. 3.
    Savarino E, Bazzica M, Zentilin P, Pohl D, Parodi A, Cittadini G, et al. Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring. Am J Respir Crit Care Med. 2009;179:408–13.CrossRefPubMedGoogle Scholar
  4. 4.
    Christmann RB, Wells AU, Capelozzi VL, Silver RM. Gastroesophageal reflux incites interstitial lung disease in systemic sclerosis: clinical, radiologic, histopathologic, and treatment evidence. Semin Arthritis Rheum. 2010;40:241–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Patti MG, Gasper WJ, Fisichella PM, Nipomnick I, Palazzo F. Gastroesophageal reflux disease and connective tissue disorders: pathophysiology and implications for treatment. J Gastrointest Surg. 2008;12:1900–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Soares RV, Forsythe A, Hogarth K, Sweiss NJ, Noth I, Patti MG. Interstitial lung disease and gastroesophageal reflux disease: key role of esophageal function tests in the diagnosis and treatment. Arq Gastroenterol. 2011;48:91–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Morehead RS. Gastro-oesophageal reflux disease and non-asthma lung disease. Eur Respir Rev. 2009;18:233–43.CrossRefPubMedGoogle Scholar
  8. 8.
    Locke 3rd GR, Talley NJ, Fett SL, Zinsmeister AR, Melton 3rd LJ. Risk factors associated with symptoms of gastroesophageal reflux. Gastroenterology. 1997;112:1448–56.CrossRefPubMedGoogle Scholar
  9. 9.
    Swigris JJ, Brown KK, Flaherty KR. The idiopathic interstitial pneumonias and connective tissue disease-associated interstitial lung disease. Curr Rheumatol Rev. 2010;6:91–8.CrossRefGoogle Scholar
  10. 10.
    Leslie KO. Pathology of interstitial lung disease. Clin Chest Med. 2004;25:657–703.CrossRefPubMedGoogle Scholar
  11. 11.
    Kandulski A, Malfertheiner P. Gastroesophageal reflux disease-from reflux episodes to mucosal inflammation. Nat Rev Gastroenterol Hepatol. 2011;9:15–22.CrossRefPubMedGoogle Scholar
  12. 12.
    Gleeson K, Eggli DF, Maxwell SL. Quantitative aspiration during sleep in normal subjects. Chest. 1997;111:1266–72.CrossRefPubMedGoogle Scholar
  13. 13.
    Kahrilas PJ, Dodds WJ, Dent J, Haeberle B, Hogan WJ, Arndorfer RC. Effect of sleep, spontaneous gastroesophageal reflux, and a meal on upper esophageal sphincter pressure in normal human volunteers. Gastroenterology. 1987;92:466–71.PubMedGoogle Scholar
  14. 14.
    Marik PE. Aspiration pneumonitis and aspiration pneumonia. New Engl J Med. 2001;344:665–71.CrossRefPubMedGoogle Scholar
  15. 15.
    Barnes TW, Vassallo R, Tazelaar HD, Hartman TE, Ryu JH. Diffuse bronchiolar disease due to chronic occult aspiration. Mayo Clin Proc. 2006;81:172–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Poh CH, Navarro-Rodrigues T, Fass R. Treatment of gastroesophageal reflux disease in the elderly. Am J Med. 2010;123:496–501.CrossRefPubMedGoogle Scholar
  17. 17.
    Plant RL. Anatomy and physiology of swallowing in adults and geriatrics. Otolaryngol Clin North Am. 1998;31:447–88.Google Scholar
  18. 18.
    Khajanchee YS, Urbach DR, Butler N, Hansen PD, Swanstrom LL. Laparoscopic antireflux surgery in the elderly. Surg Endosc. 2002;16:25–30.CrossRefPubMedGoogle Scholar
  19. 19.
    Patti MG, Goldberg HI, Arcerito M, Bortolasi L, Tong J, Way LW. Hiatal hernia size affects lower esophageal sphincter function, esophageal acid exposure, and the degree of mucosal injury. Am J Surg. 1996;171:182–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Pilotto A, Franceschi M, Leandro G, Scarcelli C, D’Ambrosio LP, Seripa D, et al. Clinical features of reflux esophagitis in older people: a study of 840 consecutive patients. J Am Geriatr Soc. 2006;54:1537–42.CrossRefPubMedGoogle Scholar
  21. 21.
    Hamelberg W, Bosomworth PP. Aspiration pneumonitis: experimental studies and clinical observations. Anesth Analg. 1964;43:669–77.PubMedGoogle Scholar
  22. 22.
    Teabeaut 2nd JR. Aspiration of gastric contents: an experimental study. Am J Pathol. 1952;28:51–67.PubMedGoogle Scholar
  23. 23.
    Greenfield LJ, Singleton RP, McCaffree DR, Coalson JJ. Pulmonary effects of experimental graded aspiration of hydrochloric acid. Ann Surg. 1969;170:74–86.CrossRefPubMedGoogle Scholar
  24. 24.
    Glauser FL, Millen JE, Falls R. Increased alveolar epithelial permeability with acid aspiration: the effects of high-dose steroids. Am Rev Respir Dis. 1979;120:1119–23.PubMedGoogle Scholar
  25. 25.
    Schwartz DJ, Wynne JW, Gibbs CP, Hood CI, Kuck EJ. The pulmonary consequences of aspiration of gastric contents at H values greater than 2.5. Am Rev Respir Dis. 1980;121:119–26.PubMedGoogle Scholar
  26. 26.
    Stothert JC, Weaver LJ, Carrico CJ. Lung albumin content after acid aspiration pulmonary injury. J Surg Res. 1981;30:256–61.CrossRefPubMedGoogle Scholar
  27. 27.
    Popper H, Juettner F, Pinter J. The gastric juice aspiration syndrome (Mendelson syndrome). Aspects of pathogenesis and treatment in the pig. Virchows Arch A Pathol Anat Histopathol. 1986;409:105–17.CrossRefPubMedGoogle Scholar
  28. 28.
    Appel 3rd JZ, Lee SM, Hartwig MG, Li B, Hsieh CC, Cantu 3rd E, et al. Characterization of the innate immune response to chronic aspiration in a novel rodent model. Respir Res. 2007;8:87.CrossRefPubMedGoogle Scholar
  29. 29.
    Amigoni M, Bellani G, Scanziani M, Masson S, Bertoli E, Radaelli E, et al. Lung injury and recovery in a murine model of unilateral acid aspiration: functional, biochemical, and morphologic characterization. Anesthesiology. 2008;108:1037–46.CrossRefPubMedGoogle Scholar
  30. 30.
    Mitsuhashi T, Shimazaki M, Chanoki Y, Kuwahara H, Sakai T, Masuda H. Experimental pulmonary fibrosis induced by trisodium citrate and acid-citrate-dextrose. Exp Mol Pathol. 1985;42:261–70.CrossRefPubMedGoogle Scholar
  31. 31.
    Kwan M, Xu YD, Raghu G, Khalil N. Acid treatment of normal rat lungs releases transforming growth factor-beta1 (TGF-beta1) and increased connective tissue synthesis. Am J Respir Crit Care Med. 2007:175 A967.Google Scholar
  32. 32.
    Downing TE, Sporn TA, Bollinger RR, Davis RD, Parker W, Lin SS. Pulmonary histopathology in an experimental model of chronic aspiration is independent of acidity. Exp Biol Med (Maywood). 2008;233:1202–12.CrossRefGoogle Scholar
  33. 33.
    Meers CM, De Wever W, Verbeken E, Mertens V, Wauters S, De Vleeschauwer SI, et al. A porcine model of acute lung injury by instillation of gastric fluid. J Surg Res. 2011;166:e195–204.CrossRefPubMedGoogle Scholar
  34. 34.
    Wang K, Lin HJ, Perng CL, Tseng GY, Yu KW, Chang FY, et al. The effect of H2-receptor antagonist and proton pump inhibitor on microbial proliferation in the stomach. Hepatogastroenterology. 2004;51:1540–3.PubMedGoogle Scholar
  35. 35.
    D’Ovidio F, Mura M, Ridsdale R, Takahashi H, Waddell TK, Hutcheon M, et al. The effect of reflux and bile acid aspiration on the lung allograft and its surfactant and innate immunity molecules SP-A and SP-D. Am J Transplant. 2006;6:1930–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Perng DW, Chang KT, Su KC, Wu YC, Wu MT, Hsu WH, et al. Exposure of airway epithelium to bile acids associated with gastroesophageal reflux symptoms: a relation to transforming growth factor-beta1 production and fibroblast proliferation. Chest. 2007;132:1548–56.CrossRefPubMedGoogle Scholar
  37. 37.
    Mertens V, Blondeau K, Vanaudenaerde B, Vos R, Farre R, Pauwels A, et al. Gastric juice from patients “on” acid suppressive therapy can still provoke a significant inflammatory reaction by human bronchial epithelial cells. J Clin Gastroenterol. 2010;44:e230–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788–824.CrossRefPubMedGoogle Scholar
  39. 39.
    Meyer KC. Interstitial lung disease in the elderly: pathogenesis, diagnosis and management. Sarcoidosis Vasc Diffuse Lung Dis. 2011;28:3–17.PubMedGoogle Scholar
  40. 40.
    Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174:810–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Selman M, Rojas M, Mora AL, Pardo A. Aging and interstitial lung diseases: unraveling an old forgotten player in the pathogenesis of lung fibrosis. Semin Respir Crit Care Med. 2010;31:607–17.CrossRefPubMedGoogle Scholar
  42. 42.
    King Jr TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011;378:1949–61.CrossRefPubMedGoogle Scholar
  43. 43.
    Collins K, Mitchell JR. Telomerase in the human organism. Oncogene. 2002;21:564–79.CrossRefPubMedGoogle Scholar
  44. 44.
    Liu T, Hu B, Chung MJ, Ullenbruch M, Jin H, Phan SH. Telomerase regulation of myofibroblast differentiation. Am J Respir Cell Mol Biol. 2006;34:625–33.CrossRefPubMedGoogle Scholar
  45. 45.
    Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. New Engl J Med. 2007;356:1317–26.CrossRefPubMedGoogle Scholar
  46. 46.
    Tsakiri K, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci. 2007;104:7552–7.CrossRefPubMedGoogle Scholar
  47. 47.
    Mora AL, Rojas M. Aging and lung injury repair: a role for bone marrow derived mesenchymal stem cells. J Cell Biochem. 2008;105:641–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Ruzankina Y, Asare A, Brown EJ. Replicative stress, stem cells and aging. Mech Ageing Dev. 2008;129:460–6.CrossRefPubMedGoogle Scholar
  49. 49.
    Collard HR, King Jr TE. Demystifying idiopathic interstitial pneumonia. Arch Intern Med. 2003;163:17–29.CrossRefPubMedGoogle Scholar
  50. 50.
    Nathan SD, Shlobin OA, Weir N, Ahmad S, Kaldjob JM, Battle E, et al. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest. 2011;140:221–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King Jr TE, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142:963–7.PubMedGoogle Scholar
  52. 52.
    Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King Jr TE, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176:636–43.CrossRefPubMedGoogle Scholar
  53. 53.
    Pearson JE, Wilson RS. Diffuse pulmonary fibrosis and hiatus hernia. Thorax. 1971;26:300–5.CrossRefPubMedGoogle Scholar
  54. 54.
    Mays EE, Dubois JJ, Hamilton GB. Pulmonary fibrosis associated with tracheobronchial aspiration. A study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial pulmonary fibrosis of obscure etiology. Chest. 1976;69:512–5.CrossRefPubMedGoogle Scholar
  55. 55.
    Raiha I, Manner R, Hietanen E. Radiographic pulmonary changes of gastro-esophageal reflux disease in elderly patients. Age Ageing. 1992;21:250–5.CrossRefPubMedGoogle Scholar
  56. 56.
    El-Serag HB, Sonnenberg A. Comorbid occurrence of laryngeal or pulmonary disease with esophagitis in United States military veterans. Gastroenterology. 1997;113:755–60.CrossRefPubMedGoogle Scholar
  57. 57.
    Patti MG, Tedesco P, Golden J, Hays S, Hoopes C, Meneghetti A, et al. Idiopathic pulmonary fibrosis: how often is it really idiopathic? J Gastrointest Surg. 2005;9:1053–6.CrossRefPubMedGoogle Scholar
  58. 58.
    Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, et al. High prevalence of abnormal acid reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27:136–42.CrossRefPubMedGoogle Scholar
  59. 59.
    Salvioli B, Belmonte G, Stanghellini V, Baldi E, Fasano L, Pacilli AM, et al. Gastro-oesophageal reflux and interstitial lung disease. Dig Liver Dis. 2006;38:879–84.CrossRefPubMedGoogle Scholar
  60. 60.
    Raghu G, Yang ST, Spada C, Hayes J, Pellegrini CA. Sole treatment of acid gastroesophageal reflux in idiopathic pulmonary fibrosis: a case series. Chest. 2006;129:794–800.CrossRefPubMedGoogle Scholar
  61. 61.
    Linden PA, Gilbert RJ, Yeap BY, Boyle K, Deykin A, Jaklitsch MT, et al. Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation. J Thorac Cardiovasc Surg. 2006;131:438–46.CrossRefPubMedGoogle Scholar
  62. 62.
    Sweet MP, Patti MG, Leard LE, Golden JA, Hays SR, Hoopes C, et al. Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation. J Thorac Cardiovasc Surg. 2007;133:1078–84.CrossRefPubMedGoogle Scholar
  63. 63.
    Noth I, Zangan SM, Soares RV, Forsythe A, Demchuk C, Takahashi SM, et al. Prevalence of hiatal hernia by blinded MDCT in patients with IPF. Eur Respir J. 2012;39(2):344–51.CrossRefPubMedGoogle Scholar
  64. 64.
    Lee JS, Song JW, Wolters PJ, Elicker BM, King Jr TE, Kim DS, Collard HR. Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J. 2012;39(2):352–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Derk CT, Jimenez SA. Systemic sclerosis: current views of its pathogenesis. Autoimmun Rev. 2003;2:181–91.CrossRefPubMedGoogle Scholar
  66. 66.
    Sjogren RW. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum. 1994;37:1265–82.CrossRefPubMedGoogle Scholar
  67. 67.
    McCarthy DS, Baragar FD, Dhingra S, Sigurdson M, Sutherland JB, Rigby M, et al. The lungs in systemic sclerosis (scleroderma): a review and new information. Semin Arthritis Rheum. 1988;17:271–83.CrossRefPubMedGoogle Scholar
  68. 68.
    Johnson DA, Drane WE, Curran J, Cattau Jr EL, Ciarleglio C, Khan A, et al. Pulmonary disease in progressive systemic sclerosis. A complication of gastroesophageal reflux and occult aspiration? Arch Intern Med. 1989;149:589–93.CrossRefPubMedGoogle Scholar
  69. 69.
    Fagundes MN, Caleiro MT, Navarro-Rodriguez T, Baldi BG, Kavakama J, Salge JM, et al. Esophageal involvement and interstitial lung disease in mixed connective tissue disease. Respir Med. 2009;103:854–60.CrossRefPubMedGoogle Scholar
  70. 70.
    Marie I, Dominique S, Levesque H, Ducrotté P, Denis P, Hellot MF, et al. Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum. 2001;45:346–54.CrossRefPubMedGoogle Scholar
  71. 71.
    de Souza RB, Borges CT, Capelozzi VL, Parra ER, Jatene FB, Kavakama J, et al. Centrilobular fibrosis: an underrecognized pattern in systemic sclerosis. Respiration. 2009;77(4):389–97.CrossRefPubMedGoogle Scholar
  72. 72.
    Patti MG, Debas HT, Pellegrini CA. Esophageal manometry and 24-hour pH monitoring in the diagnosis of pulmonary aspiration secondary to gastroesophageal reflux. Am J Surg. 1992;163:401–6.CrossRefPubMedGoogle Scholar
  73. 73.
    Knoblich R. Pulmonary granulomatosis caused by vegetable particles. So-called lentil pulse pneumonia. Am Rev Respir Dis. 1969;99:380–9.PubMedGoogle Scholar
  74. 74.
    Crome L, Valentine JC. Pulmonary nodular granulomatosis caused by inhaled vegetable particles. J Clin Pathol. 1962;15:21–5.CrossRefPubMedGoogle Scholar
  75. 75.
    Vidyarthi SC. Diffuse military granulomatosis of the lungs due to aspirated vegetable cells. Arch Pathol. 1967;83:215–8.PubMedGoogle Scholar
  76. 76.
    Emery JL. Two cases of lentil pneumonitis. Proc R Soc Med. 1960;53:952–3.PubMedGoogle Scholar
  77. 77.
    Gill DG, Ritchie GJ. Lentil Pulmonary granulomatosis. Med J Aust. 1974;1:836–8.PubMedGoogle Scholar
  78. 78.
    Friedlander AL, Fessler MB. A 70-year-old man with migratory pulmonary infiltrates. Chest. 2006;130:1269–74.CrossRefPubMedGoogle Scholar
  79. 79.
    Epler GR. Bronchiolitis obliterans organizing pneumonia. Arch Intern Med. 2001;161:158–64.CrossRefPubMedGoogle Scholar
  80. 80.
    Lazor R, Vandevenne A, Pelletier A, Leclerc P, Court-Fortune I, Cordier JF. Cryptogenic organizing pneumonia. Characteristics of relapses in a series of 48 patients. Am J Respir Crit Care Med. 2000;162:571–7.PubMedGoogle Scholar
  81. 81.
    Drakopanagiotakis F, Polychronopoulos V, Judson MA. Organizing pneumonia. Am J Med Sci. 2008;335:34–9.CrossRefPubMedGoogle Scholar
  82. 82.
    Sadoun D, Valeyre D, Cargill J, Volter F, Amouroux J, Battesti JP. Apparently cryptogenic bronchiolitis obliterans with organizing pneumonia. Demonstration of a gastro-oesophageal reflux in 5 cases. Presse Med. 1988;17:2383–5.PubMedGoogle Scholar
  83. 83.
    Song JW, Hong SB, Lim CM, Koh Y, Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J. 2011;37:356–63.CrossRefPubMedGoogle Scholar
  84. 84.
    Kondoh Y, Taniguchi H, Katsuta T, Kataoka K, Kimura T, Nishiyama O, et al. Risk factors of acute exacerbation of idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis. 2010;27:103–10.PubMedGoogle Scholar
  85. 85.
    Wootton XC, Kim DS, Kondoh Y, Chen E, Lee JS, Song JW, et al. Viral infection in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183:1698–702.CrossRefPubMedGoogle Scholar
  86. 86.
    Daniels CE, Yi ES, Ryu JH. Autopsy findings in 42 consecutive patients with idiopathic pulmonary fibrosis. Eur Respir J. 2008;32:170–4.CrossRefPubMedGoogle Scholar
  87. 87.
    Silva CI, Müller NL, Fujimoto K, Kato S, Ichikado K, Taniguchi H, et al. Acute exacerbation of chronic interstitial pneumonia: high-resolution computed tomography and pathologic findings. J Thorac Imaging. 2007;22:221–9.CrossRefPubMedGoogle Scholar
  88. 88.
    Park IN, Kim DS, Shim TS, Lim CM, Lee SD, Koh Y, et al. Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fibrosis. Chest. 2007;132:214–20.CrossRefPubMedGoogle Scholar
  89. 89.
    Emerenziani S, Sifrim D. New developments in detection of gastroesophageal reflux. Curr Opin Gastroenterol. 2005;21:450–3.PubMedGoogle Scholar
  90. 90.
    Lee JS, Collard HR, Raghu G, Sweet MP, Hays SR, Campos GM, et al. Does chronic microaspiration cause idiopathic pulmonary fibrosis? Am J Med. 2010;123(4):304–11.CrossRefPubMedGoogle Scholar
  91. 91.
    Stoeckli SJ, Huisman TA, Seifert B, Martin-Harris BJ. Interrater reliability of videofluoroscopic swallow evaluation. Dysphagia. 2003;18:53–7.CrossRefPubMedGoogle Scholar
  92. 92.
    Ravelli AM, Panarotto MB, Verdoni L, Consolati V, Bolognini S. Pulmonary aspiration shown by scintigraphy in gastroesophageal reflux-related respiratory disease. Chest. 2006;130:1520–6.CrossRefPubMedGoogle Scholar
  93. 93.
    Crausaz FM, Favez G. Aspiration of solid food particles into lungs of patients with gastroesophageal reflux and chronic bronchial disease. Chest. 1988;93:376–8.CrossRefPubMedGoogle Scholar
  94. 94.
    Schraufnagel DE, Michel JC, Sheppard TJ, Saffold PC, Kondos GT. CT of the normal esophagus to define the normal air column and its extent and distribution. Am J Roentgenol. 2008;191:748–52.CrossRefGoogle Scholar
  95. 95.
    Ginalski JM, Schnyder P, Moss AA, Brasch RC. Incidence and significance of a widened esophageal hiatus at CT scan. J Clin Gastroenterol. 1984;6:467–70.CrossRefPubMedGoogle Scholar
  96. 96.
    Tutuian R. Update in the diagnosis of gastroesophageal reflux disease. J Gastrointestin Liver Dis. 2006;15:243–7.PubMedGoogle Scholar
  97. 97.
    Kahrilas PJ, Sifrim D. High-resolution manometry and impedance-pH/manometry: valuable tools in clinical and investigational esophagology. Gastroenterology. 2008;135:756–69.CrossRefPubMedGoogle Scholar
  98. 98.
    Oelschlager BK, Chang L, Pope 2nd CE, Pellegrini CA. Typical GERD symptoms and esophageal pH monitoring are not enough to diagnose pharyngeal reflux. J Surg Res. 2005;128:55–60.CrossRefPubMedGoogle Scholar
  99. 99.
    Metheny NA, Chang YH, Ye JS, Edwards SJ, Defer J, Dahms TE, et al. Pepsin as a marker for pulmonary aspiration. Am J Crit Care. 2002;11:150–4.PubMedGoogle Scholar
  100. 100.
    Farrell S, McMaster C, Gibson D, Shields MD, McCallion WA. Pepsin in bronchoalveolar lavage fluid: a specific and sensitive method of diagnosing gastrooesophageal reflux-related pulmonary aspiration. J Pediatr Surg. 2006;41:289–93.CrossRefPubMedGoogle Scholar
  101. 101.
    Potluri S, Friedenberg F, Parkman HP, Chang A, MacNeal R, Manus C, et al. Comparison of a salivary/sputum pepsin assay with 24-hour esophageal pH monitoring for detection of gastric reflux into the proximal esophagus, oropharynx, and lung. Dig Dis Sci. 2003;48:1813–7.CrossRefPubMedGoogle Scholar
  102. 102.
    Ufberg JW, Bushra JS, Patel D, Wong E, Karras DJ, Kueppers F. A new pepsin assay to detect pulmonary aspiration of gastric contents among newly intubated patients. Am J Emerg Med. 2004;22:612–4.CrossRefPubMedGoogle Scholar
  103. 103.
    Starosta V, Kitz R, Hartl D, Marcos V, Reinhardt D, Griese M. Bronchoalveolar pepsin, bile acids, oxidation, and inflammation in children with gastroesophageal reflux disease. Chest. 2007;132:1557–64.CrossRefPubMedGoogle Scholar
  104. 104.
    Stovold R, Forrest IA, Corris PA, Murphy DM, Smith JA, Decalmer S, et al. Pepsin, a biomarker of gastric aspiration in lung allografts: a putative association with rejection. Am J Respir Crit Care Med. 2007;175:1298–303.CrossRefPubMedGoogle Scholar
  105. 105.
    Horvath I, Hunt J, Barnes PJ, Alving K, Antczak A, Baraldi E, et al. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J. 2005;26:523–48.CrossRefPubMedGoogle Scholar
  106. 106.
    Psathakis K, Mermigkis D, Papatheodorou G, Loukides S, Panagou P, Polychronopoulos V, et al. Exhaled markers of oxidative stress in idiopathic pulmonary fibrosis. Eur J Clin Invest. 2006;36:362–7.CrossRefPubMedGoogle Scholar
  107. 107.
    Hunt J. Exhaled breath condensate: an overview. Immunol Allergy Clin North Am. 2007;27:587–96.CrossRefPubMedGoogle Scholar
  108. 108.
    Jackson AS, Sandrini A, Campbell C, Chow S, Thomas PS, Yates DH. Comparison of biomarkers in exhaled breath condensate and bronchoalveolar lavage. Am J Respir Crit Care Med. 2007;175:222–7.CrossRefPubMedGoogle Scholar
  109. 109.
    Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J. Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. Arch Intern Med. 2007;167:950–5.CrossRefPubMedGoogle Scholar
  110. 110.
    Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947–53.CrossRefPubMedGoogle Scholar
  111. 111.
    Cantu E, Appel JZ, Hartwig MG, et al. J. Maxwell Chamberlain Memorial Paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease. Ann Thorac Surg. 2004;78:1142–51.CrossRefPubMedGoogle Scholar
  112. 112.
    Davis Jr RD, Lau CL, Eubanks S, Messier RH, Hadjiliadis D, Steele MP, et al. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg. 2003;125:533–42.CrossRefPubMedGoogle Scholar
  113. 113.
    DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 2005;100:190–200.CrossRefPubMedGoogle Scholar
  114. 114.
    Sise A, Friedenberg FK. A comprehensive review of gastroesophageal reflux disease and obesity. Obes Rev. 2008;9:194–203.CrossRefPubMedGoogle Scholar
  115. 115.
    Lancaster LH, Mason WR, Parnell JA, Rice TW, Loyd JE, Milstone AP, et al. Obstructive sleep apnea is common in idiopathic pulmonary fibrosis. Chest. 2009;136:772–8.CrossRefPubMedGoogle Scholar
  116. 116.
    Tawk M, Goodrich S, Kinasewitz G, Orr W. The effect of 1 week of continuous positive airway pressure treatment in obstructive sleep apnea patients with concomitant gastroesophageal reflux. Chest. 2006;130:1003–8.CrossRefPubMedGoogle Scholar
  117. 117.
    O’Halloran EK, Reynolds JD, Lau CL, Manson RJ, Davis RD, Palmer SM, et al. Laparoscopic Nissen fundoplication for treating reflux in lung transplant recipients. J Gastrointest Surg. 2004;8:132–7.CrossRefPubMedGoogle Scholar
  118. 118.
    Sugarbaker DJ, Bueno R. Laparoscopic fundoplication in patients with end-stage disease awaiting transplantation. J Thorac Cardiovasc Surg. 2006;131:438–46.CrossRefPubMedGoogle Scholar
  119. 119.
    Gasper WJ, Sweet MP, Hoopes C, Leard LE, Kleinhenz ME, Hays SR, et al. Antireflux surgery for patients with end-stage lung disease before and after lung transplantation. Surg Endosc. 2008;22:495–500.CrossRefPubMedGoogle Scholar
  120. 120.
    Gasper WJ, Sweet MP, Golden JA, Hoopes C, Leard LE, Kleinhenz ME, et al. Lung transplantation in patients with connective tissue disorders and esophageal dysmotility. Dis Esophagus. 2008;21:650–5.CrossRefPubMedGoogle Scholar
  121. 121.
    Raghu G, Meyer KC. Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Eur Respir J. 2012;39(2):242–5.CrossRefPubMedGoogle Scholar
  122. 122.
    Raghu G. Idiopathic pulmonary fibrosis: increased survival with “gastroesophageal reflux therapy”: fact or fallacy? Am J Respir Crit Care Med. 2011;184(12):1330–2.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  2. 2.Division of Pulmonary & Critical Care MedicineUniversity of Washington Medical CenterSeattleUSA

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